The goal of this project is to examine the manner in which immunologic mechanisms may contribute to diseases of the nervous system. The cellular and humoral immune response to putative antigens in possible immunopathologic disease such as multiple sclerosis (MS) are being studied. Included in these studies have been examinations of the immune response to viruses which can commonly infect the nervous system and which could be related to the induction of immunopathologic disease processes. In addition, the immune response to antigens of myelin such as myelin basic protein (MBP) and proteolipid protein (PLP) which may represent targets of immune-mediated diseases of myelin, has been studied. T-cell response to these antigens is being examined in patients with clinically definite MS and healthy controls in members of MS multiplex families, and in identical and nonidentical twins, either concordant or discordant for MS. Various parameters of the T-cell response to myelin antigens is being examined, including the frequency, peptide specificity, and HLA restriction of the T cells. Studies of the T-cell response to the 18.5 kDa form of MBP have indicated several regions of the molecule which appear to be immunodominant. One of these regions defined by amino acids 80-100 has been studied in detail, both with respect to amino acids important for binding of the peptide to the MHC class II antigen-binding cleft, as well as, amino acids important in interacting with the T-cell receptor. Studies have been conducted which based on the modification of amino acids thought to be important in T-cell recognition have altered the T-cell response to this immunodominant peptide. These studies are currently being expanded with the thought that this may form the basis for an immunologically- specific approach to modifying the T-cell response to this MBP epitope. The cytokine profile of T-cells specific for MBP or other myelin antigens is being examined. These studies involve characterization of the cytokine profile for T-cell lines and clones reactive with myelin proteins. In addition to the 18.5 kDa form of MBP, the T-cell response to other myelin antigens and other forms of MBP is being examined. This includes studies of the C-8 form of MBP which has 6 citrulline substitutions for alanine in the 18.5 kd form. Other myelin antigens, including proteolipid protein and CNPase are being studied.